Guiding pancreatic cancer therapy by individualized epigenetics

 

Although chemotherapy remains the mainstay of systemic therapy, a large number of cancer patients fail to respond to it. About half of surgically resected pancreatic ductal adenocarcinoma (PDAC) patients relapse within a year despite adjuvant chemotherapy. By investigating tumor-cell-intrinsic chromatin accessibility patterns of resected PDAC, we discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Based on this signature, we developed “ATAC-array” – the only microarray that reads chromatin accessibility – a convenient platform obviating the time and cost of Next Generation Sequencing. We also identified HNF1b, a transcription factor displaying differential nuclear localization between patients with short vs. long DFS. Combining these two simple methodologies, ATAC-array “Prognosis Score” and HNF1b nuclear localization, we have developed an algorithm which we call PancEpistemeDx, and stratified PDAC patients into prognostic groups with up to four-fold differences in DFS. Whether adverse patterns of chromatin accessibility might assist in the selection of PDAC patients for epigenetic “reprogramming” therapy remains to be determined, but our stratification provides a simple and clinically achievable prediction of favorable vs unfavorable epigenetic states in PDAC. Episteme Prognostics aims to 1) optimize PancEpistemeDx for routine clinical use and expand it to all stages of pancreatic cancer, and 2) develop companion diagnostics (CDx) for epigenetic drugs. We sit at the dawn of the epigenetic drug discovery era, the FDA has already approved 9 epigenetic drugs, and currently, 138 clinical trials on epigenetic drugs are registered by 31 different pharmaceutical companies. Our technology can support therapeutic decision-making in pancreatic cancer clinics, as well as can support clinical trials on epigenetic drug discovery for pharma companies.

 

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For Research Use Only. Not for use in diagnostic procedures.